 | |
 | |
| Clinical data | |
|---|---|
| Other names | 3-Trifluoromethylamphetamine; 3-TFMA; Desethylfenfluramine; JP-92 |
| Identifiers | |
| |
| CAS Number | |
| PubChemCID | |
| IUPHAR/BPS | |
| ChemSpider |
|
| UNII | |
| ChEBI | |
| ChEMBL | |
| CompTox Dashboard(EPA) | |
| Chemical and physical data | |
| Formula | C10H12F3N |
| Molar mass | 203.208 g·mol−1 |
| 3D model (JSmol) | |
| |
| |
| (verify) | |
Norfenfluramine, or3-trifluoromethylamphetamine, is a never-marketeddrug of theamphetamine family and a majoractive metabolite of theappetite suppressantsfenfluramine andbenfluorex. Thecompound is aracemic mixture of twoenantiomers with differing activities,dexnorfenfluramine andlevonorfenfluramine.[1][2]
Norfenfluramine acts as aserotonin–norepinephrine releasing agent (SNRA)[3][1] and as apotent serotonin5-HT2A,5-HT2B, and5-HT2C receptoragonist.[4] Bothenantiomers of norfenfluramine are active asmonoamine releasing agents, althoughdexnorfenfluramine is more potent thanlevonorfenfluramine.[1] Similarly, both enantiomers are active as serotonin5-HT2 receptor agonists, but dexnorfenfluramine is likewise more potent than levonorfenfluramine.[4]
Norfenfluramine is of similar potency as fenfluramine as a serotonin releaser but is substantially more potent as a norepinephrine anddopamine releaser.[3][1] The drug is also far more potent than fenfluramine as an agonist of the serotonin 5-HT2 receptors.[4]
The action of norfenfluramine on serotonin 5-HT2B receptors onheart valves leads to a characteristic pattern ofheart failure followingproliferation ofcardiacfibroblasts on thetricuspid valve, known ascardiac fibrosis.[5] Thisside effect led to thewithdrawal offenfluramine as ananorectic medication worldwide and to the withdrawal ofbenfluorex inEurope.[6]
In spite of acting as a serotonin 5-HT2A receptor agonist, norfenfluramine is described as non-hallucinogenic.[7] However, hallucinations have occasionally been reported with large doses of fenfluramine, which itself is a much weaker serotonin 5-HT2A receptor agonist than norfenfluramine but produces norfenfluramine as a major active metabolite.[7] Dexnorfenfluramine produces thehead-twitch response, a behavioral proxy ofpsychedelic effects, in rodents.[8]
Norfenfluramine has been found to act as an agonist of thetrace amine-associated receptor 1 (TAAR1).[9] Dexnorfenfluramine is a very weak human TAAR1 agonist (43% of maximum in screen at a concentration of 10,000 nM), whereas levonorfenfluramine is inactive as a human TAAR1 agonist.[9]
| Compound | NETooltip Norepinephrine | DATooltip Dopamine | 5-HTTooltip Serotonin | Ref |
|---|---|---|---|---|
| Dextroamphetamine | 6.6–7.2 | 5.8–24.8 | 698–1,765 | [10][11][12][13] |
| Levoamphetamine | 9.5 | 27.7 | ND | [14][12][15][16] |
| Dextromethamphetamine | 12.3–14.3 | 8.5–40.4 | 736–1,292 | [10][17][12][18] |
| Levomethamphetamine | 28.5 | 416 | 4,640 | [10][12] |
| Dextroethylamphetamine | 28.8 | 44.1 | 333.0 | [19][20] |
| Fenfluramine | 739 | >10,000 (RI) | 79.3–108 | [3][21][10][1] |
| Dexfenfluramine | 302 | >10,000 | 51.7 | [3][21][10][1] |
| Levfenfluramine | >10,000 | >10,000 | 147 | [3][21][1][22] |
| Norfenfluramine | 168–170 | 1,900–1,925 | 104 | [3][21][1][2] |
| Dexnorfenfluramine | 72.7 | 924 | 59.3 | [3][21][1] |
| Levnorfenfluramine | 474 | >10,000 | 287 | [3][21][1] |
| Phentermine | 28.8–39.4 | 262 | 2,575–3,511 | [10][12][18] |
| Chlorphentermine | >10,000 (RI) | 935–2,650 | 18.2–30.9 | [10][18] |
| Notes: The smaller the value, the more strongly the drug releases the neurotransmitter. Theassays were done in rat brainsynaptosomes and humanpotencies may be different. See alsoMonoamine releasing agent § Activity profiles for a larger table with more compounds.Refs:[23][3][21] | ||||
| Compound | 5-HT2A | 5-HT2B | 5-HT2C | ||||||
|---|---|---|---|---|---|---|---|---|---|
| Ki (nM) | EC50Tooltip Half-maximal effective concentration (nM) | EmaxTooltip Maximal efficacy (%) | Ki (nM) | EC50Tooltip Half-maximal effective concentration (nM) | EmaxTooltip Maximal efficacy (%) | Ki (nM) | EC50Tooltip Half-maximal effective concentration (nM) | EmaxTooltip Maximal efficacy (%) | |
| Fenfluramine | 5,216 | 4,131 | 15% | 4,134 | ND | ND | 3,183 | ND | ND |
| Dexfenfluramine | 11,107 | >10,000 | ND | 5,099 | 379 | 38% | 6,245 | 362 | 80% |
| Levofenfluramine | 5,463 | 5,279 | 43% | 5,713 | 1,248 | 47% | 3,415 | 360 | 84% |
| Norfenfluramine | 2,316 | ND | ND | 52.1 | ND | ND | 557 | ND | ND |
| Dexnorfenfluramine | 1,516 | 630 | 88% | 11.2 | 18.4 | 73% | 324 | 13 | 100% |
| Levonorfenfluramine | 3,841 | 1,565 | 93% | 47.8 | 357 | 71% | 814 | 18 | 80% |
| Phentermine | >10,000 | IA orND | IA orND | >10,000 | IA orND | IA orND | >10,000 | 1,394 | 66% |
| Chlorphentermine | ND | >10,000 | ND | ND | 5,370 | ND | ND | 6,456 | ND |
| Notes: (1) The smaller the Ki or EC50 value, the more avidly the drug binds to or activates the receptor. The higher the Emax value, the more effectively the drug activates the receptor. (2) All values are for human receptors except for the 5-HT2A and 5-HT2C Ki values, which are for the rat receptors.Refs:[4][21][3] | |||||||||
The most commonly studied DAT substrates are amphetamines, including amphetamine and methamphetamine (Fig. 9). S-(+)-amphetamine releases dopamine with an EC50 of 8.7 nM; the R-(−)-amphetamine is 3-fold weaker, at 27.7 nM (EC50) (Blough, Page et al. 2005). Although weaker, a similar trend is seen for the optical isomers of methamphetamine. S-(+)-methamphetamine releases dopamine with an EC50 of 24.5 nM, while the R-(−)-methamphetamine is 16-fold less active at 416 nM (EC50) (Blough, Page et al. 2005). [...] Blough, B. E., K. M. Page, et al. (2005). "Struture-activity relationship studies of DAT, SERT, and NET releasers." New Perspectives on Neurotransmitter Transporter Pharmacology.
RESULTS. Methamphetamine and amphetamine potently released NE (IC50s = 14.3 and 7.0 nM) and DA (IC50s = 40.4 nM and 24.8 nM), and were much less potent releasers of 5-HT (IC50s = 740 nM and 1765 nM). Phentermine released all three biogenic amines with an order of potency NE (IC50 = 28.8 nM)> DA (IC50 = 262 nM)> 5-HT (IC50 = 2575 nM). Chlorphentermine was a very potent 5-HT releaser (IC50 = 18.2 nM), a weaker DA releaser (IC50 = 935 nM) and inactive in the NE release assay. Chlorphentermine was a moderate potency inhibitor of [3H]NE uptake (Ki = 451 nM). [...]
FIGURE 2-6: Release: Effects of the specified test drug on monoamine release by DAT (red circles), NET (blue squares), and SERT (black traingles) in rat brain tissue. [...] EC50 values determined for the drug indicated within the panel. [...]
